Hemostasis, the control of bleeding, is effectuated either by surgical means or by affecting the physiological state of blood vessels or the coagulation. This invention particularly concerns blood coagulation and its role in maintaining the functioning of the human organism after injury, inflammation, disease, congenital defect, dysfunction, or other disruption.
Thrombin is a key protein responsible for the coagulation.
Thrombin plays the main role in thrombosis due to its ability to catalyze the conversion of fibrinogen into fibrin.
Direct and indirect inhibitors of thrombin till recently have been the focus of a variety of anticoagulant strategies, e.g., Claeson, G., “Synthetic Peptides and Peptidomimetics as Substrates and Inhibitors of Thrombin and Other Proteases in the Blood Coagulation System”, Blood Coag. Fibrinol. 5, 411-436 (1994). Several classes of anticoagulants currently used in the clinic are direct or indirect inhibitors of thrombin (heparin, low-molecular-weight heparin, coumarins, etc.).
A prothrombinase complex, comprising the protein (factor Xa) converts a proenzyme prothrombin into the active thrombin. Factor Xa belongs to a class of serine proteases and is formed from the protein (factor) X due to activation thereof. Unlike thrombin, which acts on a variety of protein substrates and specific receptors, factor Xa evidently acts on a single substrate, namely prothrombin. Since one molecule of factor Xa is able to generate up to 138 molecules of thrombin, direct inhibitors of protein Xa, as inhibitors of formation of thrombin may be used as efficient agents in the anticoagulant strategy. Therefore, it is obvious that agents, which selectively inhibit protein Xa, may be useful as in vitro diagnostic agents, or as therapeutic agents against diseases associated with coagulation.
Polypeptides derived from hematophagous organisms may be efficient and inhibitors of factor Xa. U.S. Pat. No. 4,588,587 describes the anticoagulant activity of the saliva of the Mexican leech, Haementeria officinalis. The active agent of this saliva is the polypeptide factor Xa inhibitor, antistasin (ATS), another potent and highly specific inhibitor of Factor Xa, called tick anticoagulant peptide (TAP), has been isolated from the whole body extract of the soft tick Ornithidoros moubata. 
Factor Xa inhibitory compounds, which are not polypeptides, have also been prepared, according to: Tidwell, R. R. et al., “Strategies for Anticoagulation With Synthetic Protease Inhibitors. Xa Inhibitors Versus Thrombin Inhibitors”, Thromb. Res., 19, 339-349 (1980); Turner, A. D. et al., “p-Amidino Esters as Irreversible Inhibitors of Factor IXa and Xa and Thrombin”, Biochemistry, 25, 4929-4935 (1986); Hitomi, Y. et al, “Inhibitory Effect of New Synthetic Protease Inhibitor (FUT-175) on the Coagulation System”, Haemostasis, 15, 164-168 (1985); Sturzebecher, J. et al., “Synthetic Inhibitors of Bovine Factor Xa and Thrombin. Comparison of Their Anticoagulant Efficiency”, Thromb. Res., 54, 245-252 (1989); Kam, C. M. et al., “Mechanism Based Isocoumarin Inhibitors for Trypsin and Blood Coagulation Serine Proteases: New Anticoagulants”, Biochemistry, 27, 2547-2557 (1988); Hauptmann, J. et al., “Conzparisofz of the Anticoagulant and Antithrombotic Effects of Synthetic Thrombin and Factor Xa Inhibitors”, Thromb. Haemost., 63, 220-223 (1990); and the like.
Others have reported Factor Xa inhibitors, which are small molecule organic compounds, such as nitrogen containing heterocyclic compounds which have amidino substituent groups, wherein two functional groups of the compounds can bind to Factor Xa at two of its active sites. For example, WO 98/28269 describes pyrazole compounds having a terminal C(═NH)—NH2 group; WO 97/21437 describes benzimidazole compounds substituted by a basic radical which are connected to a naphthalene group via a straight or branched chain alkylene, —C(═O) or —S(═O) 2 bridging group; WO 99/10316 describes compounds having a 4-phenyl-N-alkylamidino-piperidin connected to a 3-amidinophenyl group via a carboxamidealkyleneamino bridge; and EP 798295 describes compounds having a 4-phenoxy-N-alkylamidino-piperidine group connected to an amidinonaphthyl group via a substituted or unsubstituted sulfonamides.
Still, there exists a need for effective therapeutic agents for the regulation of hemostasis, and for the prevention and treatment of thrombus formation and other pathological processes in the vasculature induced by thrombin such as restenosis and inflammation. In particular, there continues to be a need for compounds which selectively inhibit protein Xa. Compounds with a higher degree of binding to protein Xa than to thrombin are especially preferable if they have a good bioavailability and/or solubility.